Multifunctionalized polyethylene glycol derivative and preparation method therefor

Abstract

Disclosed are a multifunctionalized polyethylene glycol derivative and a preparation method therefor. The derivative has an H-shaped structure as represented by formula (1) and comprises one linear core LPEG and four PEG branch chains, where n1, n2, n3, and n4 respectively are the degrees of polymerization of the branch chains, U1 and U2 are trivalent branching groups connecting the core LPEG to two of the PEG branch chains, F1 and F2 contain a functional group or a protected form R01 thereof and may or may not contain a branched group G, correspondingly, the number of R01 is one or more, F1 and F2 are either identical or different, any one linking group in the molecule or any linking group formed with an adjacent heteroatom group can either remain stable or be degraded, and any one PEG segment in the molecule is discretely polydispersed or monodispersed. The multifunctional polyethylene glycol is flexible and diverse in terms of branch structures and the lengths of branching arms, has various parameters and performance indicators that are adjustable and easy to control, and has a broad applicability.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a U.S. National Phase Application of International Application No. PCT / CN2015 / 091193, filed Sep. 30, 2015 which claims priority to Chinese Application Nos. 201410526707.6, filed Oct. 1, 2014 and 201510349134.9, filed Jun. 23, 2015.TECHNICAL FIELD[0002]The present invention relates to the field of polymer synthesis, especially a multifunctionalized polyethylene glycol compound, substance thereof and production methods thereof.BACKGROUND OF THE INVENTION[0003]PEGylation has been widely recognized as one of the most important approaches for drug modification. Wherein, Functionalized PEGs, owing to their active groups, are capable of modifying therapeutic drugs and bio-related substances by covalently binding to target molecules, normally small molecule organic drugs or biomolecules, including proteins, peptides, saccharides, lipids, oligonucleotides, affinity ligands, cofactors, liposomes, biomaterials and the like. The p...

AI Technical Summary

Benefits of technology

The present invention introduces several beneficial effects: (i) The use of linear polyethylene glycols as initiators allows for the synthesis of novel initiators with diverse structures and characteristics; (ii) Compared with conventional small molecular initiators, initiators based on linear polyethylene glycols provide more manners and advantages in the aspect of isolation and purification; (iii) The H-shaped design can modulate the distance between branch chains of two sides via changing the length of linear main chain, and help control properties of H-shaped multifunctionalized polyethylene glycols of a given molecular weight by regulating respective lengths of main chain and branch chains; (iv) The reaction efficiency would be increased when modifying drugs; (v) The combination of diversity in production methods and quantity in active sites, allows modification of two different drugs in one molecule or introduction of functional moieties capable of promoting pharmaceutical efficacy； (vi) The H-shaped functionalized polyethylene glycol in the present invention, degradable groups can be flexibly introduced into its structure or a pegylated bio-related substance thereof in the subsequent applications； (vii) The heterofunctionalized design allows unpegylated bio-related substance to be terminated by hydroxyl groups in place of methoxy groups in order to reduce the immunogenicity of pegylated drugs, and to decrease toxic side effects and improve tissue distribution profile of drugs; (viii) The introduction of targeting factors can improve tissue distribution profile of drugs and weaken adverse effects against normal tissues, and facilitate the detection of pharmacokinetics, tissue distribution of drugs, etc. The invention also allows for the combination of multiple functional groups in one molecule, providing more flexibility in drug modification and application.

Problems solved by technology

The conventionally commercial branched polyethylene glycol derivatives with two polyethylene glycol chains, representively “V-shaped”, only has a single active group capable of reacting with drug molecules, which result in low drug loading and very limited applications.

Furthermore, with respect to pegylated drugs, because the binding site may be located at or nearby the active moiety, or because of the introduction of steric effect, it is most likely to result in decrease or disappearance of activities of pegylated drugs.

What's more, for conventional administration methods, such as parenteral administration, oral administration, etc., the drug molecules not only act on the lesion site, but also accumulate in normal tissues, and thus cause somewhat or very severe toxic side effects.

Although the toxic side effects can be greatly reduced via pegylation for many drugs, the biosafety requirement for some drugs especially for anticancer drugs still cannot be satisfied by using available pegylation technique.

Furthermore, problems such as how to improve the maintenance of drug activity, or how to realize release of highly active drugs are urgently to be improved or resolved.

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